1. Field of the Invention
The present invention relates to methods and reagents for identifying patients at risk for developing a systemic inflammatory condition, such as sepsis.
2. Description of Related Art
Early detection of the presence of disease conditions in patients typically allows more effective therapeutic treatments and results in more favorable clinical outcomes than occur when disease conditions are not recognized until an advanced stage. Unfortunately, the early detection of disease symptoms in many instances is problematic, and a disease may be relatively advanced before clinical suspicion of the disease occurs.
Systemic inflammatory conditions represent one class of diseases for which early diagnosis is particularly desirable, with sepsis being the most serious, and perhaps the most difficult to clinically diagnose. Sepsis is the result of the interaction of a pathogenic microorganism with a host's defense system that leads to systemic inflammation. Characterizing sepsis in a host, however, is made very complex by the number and heterogeneity of factors that play into the final outcome. The presence of underlying disease, a patient's genetically determined response to inflammatory stimuli, the general status of his/her immune system, and the microbial mediators and virulence factors released by infectious organisms, among other factors, all contribute to the disease course. The process by which this occurs is often remarkably rapid, leaving the clinician with little time to make a considered clinical judgment.
More significant yet is the high morbidity and mortality associated with sepsis. The incidence of sepsis has been increasing in the last 20 years and current figures indicate the presence of 750,000 cases per year of severe sepsis in the United States alone (Angus, D C et al. Crit. Care Med. 29:1303-1310 [2001]). The estimated crude mortality is 35%, all comorbidities being considered (Rangel-Frausto, M S. Infectious Disease Clinics of North America 13(2):299-312 [1999]). Sepsis is the 10th leading cause of death in the United States, and among hospitalized patients in noncoronary intensive care units, has been reported to be the most common cause of death. The disease accounts for an estimated $16 billion in annual health care expenditures in the United States alone. For the clinical practitioner, these epidemiologic and economic statistics place a high premium on making a correct and rapid clinical judgment in an arena where the clinician frequently has little more at his/her disposal than broad, non-specific clinical guidelines fortified by his or her own clinical experience.
Diagnosing sepsis at a point in time when the clinician can intervene with preventive measures has been and continues to be a very challenging task. Investigators point out that disease definitions that are too broad limit the ability of clinicians to direct appropriate therapies at patients who are at high risk for developing sepsis. In addition, these definitions do not permit the clinician to differentiate between an at risk patient who may derive a net benefit from a new, expensive therapy and a patient who will either not benefit, given his/her underlying disease co-morbidities, or who may be placed at higher risk from the therapy's inherent safety profile.
Sepsis typically results from the spread of a localized nidus of infection to the systemic circulation. Under these conditions, beneficial local inflammatory processes, mediated by specialized white blood cells such as neutrophils and monocytes and the factors they produce, and which are normally present to control the spread of the infectious focus, may expand their spheres of activity into life-threatening systemic inflammation. The course by which a patient progresses either to death or hospital discharge is well-known and has been described as a continuum from a state termed systemic inflammatory response syndrome (SIRS) to successive states of sepsis, severe sepsis, septic shock, multiple end-organ failure (MODS) and death (Rangel-Frausto, M S. JAMA 11:117-123 [1995]).
As a result of a recent consensus conference sponsored by the American College of Chest Physicians (Crit. Care Med. 20:864-874 [1992]), a uniform set of definitions for states associated with the sepsis syndrome was proposed. Systemic inflammatory response syndrome or SIRS is considered the accepted term for a clinical state in which two or more of the following clinical parameters are present: body temperature >38° C. or <36° C.; heart rate >90 beats/minute; respiratory rate >20 breaths/minute, or a PCO2<32 mm Hg; and white blood cell count >12,000/mm3, <4000/mm3, or having >10% immature band forms. Sepsis is understood to be SIRS with a confirmed infectious process (positive culture). Severe sepsis is sepsis associated with organ dysfunction, hypoperfusion abnormalities, or hypotension. Hypoperfusion abnormalities include, but are not limited to, lactic acidosis, oliguria and mental status changes. Septic shock is understood to be sepsis-induced hypotension resistant to fluid resuscitation, and, having, in addition, the presence of hypoperfusion abnormalities.
Part of the challenge of classifying patients as septic is documenting the presence of a clinically significant microorganism. This is typically performed by culturing the patient's blood, sputum, urine, wound secretions, in-dwelling line surfaces, etc. Because many microorganisms require specialized conditions to promote their rapid growth, and may be more commonly present in certain body microenvironments, and because microbe numbers may initially be low at the site of infection, cultures are not always positive, even when a microorganism may be present. Thus, blood cultures, for example, may be positive only 17% of the time in patients that present with the clinical manifestations of sepsis (Rangel-Frausto, M S et al. JAMA 273: 117-123 [1995]). Moreover, cultures can also be inadvertently contaminated with microorganisms that are generally known to be non-pathogenic. In a study of 843 episodes of positive blood cultures from 707 patients with septicemia, only 12.4% of the coagulase-negative class of Staphylococci, for example, were clinically significant (Weinstein, M P et al. Clinical Infectious Diseases 24: 584-602 [1997]). Because of the difficulty of obtaining positive clinically significant cultures, investigators have defined culture-negative sepsis as SIRS with administration of empiric antibiotics under conditions where an infection is suspected but not confirmed by cultures (Rangel-Frausto, M S et al. JAMA 273: 117-123 [1995]).
The very complexity of the process of sepsis and the lack of clinically-relevant animal models have not only hampered the clinical community's ability to develop consensus definitions around the disease's characteristics, but have also slowed the pace of pharmaceutical progress in the field. Investigators point out that the field of sepsis clinical research has suffered from a long series of failed clinical trials that attempted to evaluate new treatment methodologies. The reasons why these trials failed are varied but one common theme that emerges is that many trial designs were based on animal model evidence that was of unknown clinical significance. Thus, because of differences between animal models of sepsis and human sepsis, for example, anti-inflammatory cytokine treatments may have been administered at a point in the patients' history when the patients were actually in a state of immune paralysis with undetectable levels of proinflammatory cytokines. In these settings, patients may not only fail to benefit from the treatment, but may be placed at increased risk from the treatment's inherent side effects, without the potential for an upside gain. The lack of ability to prospectively identify the patient cohort most likely to benefit from a therapy has hampered the implementation of rational timing and dosing regimens, and hence, outcomes have been dismal. Animal model experience, unfortunately, has not been a reliable guide for treatment timing and dosing regimens for humans (Opal, S M and Cross, A S. Infectious Disease Clinics of North America 13 (2): 285-297 [1999])
In addition to having consensus definitions, many clinicians would agree that what are most needed are assays to distinguish patients who display SIRS criteria, such as fever, and who will resolve without developing sepsis, from those patients who display SIRS criteria and who will progress to sepsis. In addition, other useful assays would identify patients who are most likely to benefit from a specific sepsis therapy, given existing comorbidities.
With respect to these points, most of the scoring systems and/or predictive models for sepsis that the clinician currently has at his/her disposal are oriented at, or utilized by, practitioners who intend to predict disease outcome in the patient who is already considered septic, and provide no indication of sepsis prior to its clinical onset. Reviewed by Roumen, R L et al. (J. Trauma 35: 349-355 [1993]), these scoring systems include the Injury Severity Score (ISS, 1974) which is a measure of the severity of blunt trauma injury to five major body systems, the Glasgow Coma Scale (SCS, 1974) which measures mental status changes, the Trauma Score (1980) which extends the Glasgow score to include respiratory and hemodynamic parameters, the TRISS method which combines physiologic and anatomic measurements to assess probability of surviving an injury, the Sepsis Severity Score (1983) which grades the functioning of seven body organs, the Polytrauma Score (1985) which adds an age parameter to the Injury Severity Score, the Multiple Organ Failure (MOF) Score (1985) which assesses the function of seven major organ systems and the APACHE II (1985). The latter is a comprehensive scoring system, which draws on data from a number of routinely measured physiological assessments in addition to a general health status score and an age score. APACHE, APACHE II, and its more recent version APACHE III, are typically used to predict the risk of death in certain groups of severely ill patients.
All of the aforementioned scoring systems, including the APACHE systems, show varying degrees of correlation with the outcomes of survival and death in sepsis patients. In a comparison of a number of these systems, Roumen, R M et al. (J. Trauma 35: 349-355 [1993]) concluded that the predictive value of a number of the severity scoring systems most appropriately addresses the identification of patients who will suffer late-stage complications of sepsis, not the presence or development of sepsis itself. Systems that measured physiologic response to trauma were not considered predictive as to late-stage outcome.
Various biological markers are known to be indicative of sepsis, and use of one or more biological markers to distinguish groups of patients who are septic from groups of patients who may have SIRS but are not septic has been reported. Many studies can be cited in which a group of septic patients is shown retrospectively to differ in its average level of a given marker from either a group of normal volunteers or a set of hospitalized controls. Other studies attempt to retrospectively differentiate groups of patients at various stages in the sepsis disease continuum from each other. Takala, A et al. (Clin. Sci. 96, 287-295 [1999], for example, have shown that groups of patients that are positive for two or more SIRS criteria can be distinguished from each other and from septic patients as well as from healthy controls by levels of selected biological markers. Based on each marker's levels in a given patient, a whole number subscore, known as the Systemic Inflammation Composite Score (SICS), is calculated. Statistically significant differences in SICS have been shown to exist between groups of patients with 2 positive SIRS criteria vs. 3 positive SIRS criteria vs. a group of septic patients. The SICS scoring system, however, is not intended to, and does not provide effective modeling for individual patients to detect when and if a given patient has become septic.
A method for the detection of septic shock and organ failure is described in Slotman, G J (Critical Care 4: 319-326 [2000]) and for systemic inflammatory conditions in general in U.S. Pat. No. 6,190,872. This method involves the daily measurement of selected biological markers in a model-building cohort of patients in an intensive care unit (ICU). A separate, unique predictive model is generated for each day of ICU stay. In constructing the model for a particular day, the same set of markers are used for each and every patient. However, models generated for different days may use different sets of markers. Each model applies to all patients who have been in the ICU the same number of days. This type of modeling fails to account for the variability in patient condition and rate of disease progression following admittance to the ICU. Furthermore, use of different models on each day makes it difficult to monitor patient progress.